Uncovering genetic predisposition to early onset dementia in patients with Parkinson’s disease/
The main purpose of this project is to investigate the effect of genetic variation in the progression of Parkinson’s disease. Parkinson’s disease (PD) is characterized as a movement disorder, with the cardinal motor features of bradykinesia, rigidity and resting tremor reflecting dysfunction within dopaminergic nigrostriatal circuity. However, non-motor symptoms also constitute a significant part of the symptom burden in PD, and cognitive dysfunction is the most relevant non-motor symptom that affects patients’ quality of life. About 50% of patients develop dementia after 10 years into their illness; however, the patterns of cognitive impairment and their speed of evolution vary varies markedly between individuals. Cognitive deficits in PD are heterogeneous in terms of the domains affected, including executive dysfunction, memory, and visuospatial impairments. Several studies have demonstrated that early dysfunction on neuropsychological tests with a posterior cortical basis predicts more rapid progress to dementia, whilst frontostriatally based executive deficits were not associated with earlier dementia. Moreover, neuroimaging demonstrates that atrophy in posterior cortical regions precedes cognitive decline in longitudinal studies, and this posterior cortical dysfunction can predict dementia. The genetic contribution to PD has been shown to play an important role, and a number of common genetic variants have been identified to contribute to cognitive function in PD. In this part of the study, we investigated if the most common mutations reported to be associated with progression to dementia in PD are also associated with dementia in the ParkVest cohort. We selected five mutations in four genes: BDNF (rs6265), MAPT (rs1800457), APOE (rs429358 and rs7412) and COMT (rs4680). In order to study the cognitive deficits in PD, and the effect of these mutations in each domain, neuropsychological tests were analysed against mutation status carrier. So far, we have achieved the following results: a) Basic Association analyze for the five mutations in ParkVest; b) Cox proportional hazard model adjusting for age, gender and education to measure the rate of progression to dementia in mutation carriers, and; c) Repeated-measure regression analysis to assess longitudinal association between genotype and cognitive progression score follow up 7 years. We analyzed five different criteria: 1. Global cognition, 2. Executive function, 3. Learning and memory, 4. Visuospatial, 5. Attention.
The main purpose of this project is to investigate the effect of genetic variation in the progression of Parkinson’s disease. Parkinson’s disease is one of the most common neurodegenerative diseases among the elderly, and is characterized by motor disturbance and nonmotor symptoms, including cognitive impairment that can lead to the development of dementia. Studies suggest that individuals with Parkinson’s disease have a 3-5 times higher risk of developing dementia. The genetic contribution to cognitive impairment in Parkinson’s disease, and whether there are genetic factors that can protect or increase the risk of progression to dementia, remains unclear. Genetic studies and association analysis in other neurodegenerative diseases, such as Alzheimer’s disease, have identified many variants associated with dementia. Taken together these studies support a genetic contribution to cognitive impairment and reveal a list of genes associated with dementia. In this project, we first investigated the genetic variability in ~ 1000 selected genes related to Parkinson’s disease or cognitive decline, using a Target Exome Sequencing approach. Our goal was to identify particular genetic variants among patients with Parkinson’s disease who developed dementia rapidly after disease onset. With the purpose of increasing the power of our study, we subsequently sequenced in a collaborative effort the whole exome of each patients with Parkinson’s disease. Furthermore, this approach allowed us the possibility to study the contribution of variants to cognitive decline and dementia using an unbiased approach. So far, we have achieved the following results: a) For the targeted exome sequencing analysis we have: 1. validated the variants overrepresented in the dementia group by genotyping the whole cohort (384 patients and control subjects); and 2. constructed C. elegans strains harboring variants validated in the whole cohort , to further study the biological effect of these variants in this model organism. b) For the whole exome sequencing analysis we have: 1. Set up bioinformatics pipelines (including PLINK, PLINKSEQ, EPACT, ANNOVAR) for association analyses; 2. validated the single nucleotide variants and insertions/deletions and annotated the variants in the whole-exome sequencing data from 192 patients, and; 3. Described the variability of the candidate genes involved in dementia in the whole cohort. Next we will perform association analysis and burden testing for the variants in the candidate genes in respect to decline in cognitive function, and the onset of dementia.
One of the main aims of this project, is to investigate how genetic variation affects the observed differences in disease progression among patients with Parkinson's Disease. Parkinson's disease (PD) is a complex, progressive, neurodegenerative disorder that affects more than 1% of people over 60. While 99.9% of human DNA sequence is identical, variability in our DNA sequence can distinguish among individuals, and a small fraction of these differences can influence disease progression. Long-term observational studies demonstrate that 80% of patients with PD may eventually develop dementia (PDD); however, the progression of the disease varies greatly from one patient to another. One of the critical needs in PD is the development of a practical and accurate prognostic test to enable the early identification of patients at risk of PDD. In this project we set out to uncover the genetic variability among patients with PD, to identify DNA variations that distinguish between individuals who developed dementia relatively quickly after PD diagnosis, and individuals who remained cognitively normal. The first step of this project was to sequence ~1000 genes related to Parkinson’s disease or cognitive decline in two groups of patients with PD, one that developed early dementia, and another that remained cognitively normal in the same period after diagnosis. To date we have: 1) captured the DNA regions of the ~1000 candidate genes; 2) sequenced the selected regions using Targeted Exome Sequencing; 3. analysed bioinformatically the sequencing results and identified genetic variants present in individuals of the two groups; 4. identified a set of genetic variants that are overrepresented in individuals with early diagnosis of PDD but absent from cognitively normal individuals, and; 5. selected the most interesting variants for further analysis, focusing on those DNA differences that are most likely to effect protein structure and function. These DNA variations are currently being followed up in larger number of individuals to discover whether there is a statistical association between the frequency of any of these genetic variants and specific patterns of disease progression, with special focus on the rate of development of PDD.